1. Field of the Invention
The present invention relates to a method and device for inducing locomotion in animals by epidural and subdural stimulation of the cervical and lumbar enlargements of the spinal cord.
2. The Prior Art
Electrical stimulation of the human spinal cord, usually epidurally, has been used for many years to treat chronic pain and abnormal motor control. The bulk of the use of spinal cord stimulation has been directed at pain relief and entails implantation of electrodes along the dorsal (posterior) aspect of the spinal cord along the length of the dorsal (posterior) columns. For certain patients, this has proved successful in alleviating chronic pain. Spinal cord stimulation also has been used in treating multiple sclerosis, spinal cord injury, cerebral palsy, amyotrophic lateral sclerosis, dystonia, torticollis and other neurological disorders. The aim of such stimulation has been to attempt to control or reduce abnormal movements such as spasticity and rigidity. Some success has been reported in using spinal cord stimulation in bladder dysfunction. The use of electrical stimulation of peripheral nerves and spinal cord to promote recovery from trauma and to accelerate nerve regeneration also has been proposed. To the knowledge of the inventors, there are no reports on the successful use of spinal cord stimulation to induce locomotion, that is, of the use of prosthetic spinal cord stimulation to control stepping movements, especially in the case of a completely severed spinal cord.
The usual placement of epidural electrodes is near the affected (painful) dermatome segment. Implantation techniques vary from the use of laminectomy to catheterization via epidural needle. The parameters of stimulation are usually comprised of pulses of short duration, typically 0.05 msec to 0.5 msec, delivered at high frequency, typically 10 Hz to 2000 Hz at voltage amplitudes set by the patient as needed, usually in the range of 1 v to 15 v. Several companies produce various forms of spinal cord stimulators (Avery Labs., Cordis Corp., Medtronic Inc. and Neuromed Corp.). Some of these types of stimulators will be briefly discussed below, particularly with respect to their stimulus capabilities. These differ in the number of electrodes which can be controlled and in the ranges of the stimulus parameters that they are capable of generating. Units may be powered and controlled through radio frequency coupling from an externally powered unit or be totally implantable (see Sherwood, 1988).
The following is a list of patents and journal articles which relate to the electrical stimulators in use for the treatment of pain and movement disorders. Each will be discussed below.
______________________________________ Patent No. Inventor Patent No. Inventor ______________________________________ 3,654,933 Hagfors 4,539,993 Stanton 3,724,467 Avery et al. 4,558,703 Mark 3,822,708 Zilber 4,598,7I3 Hansjurgens et al. 3,920,025 Stasz et al. 4,649,935 Charmillot et al. 4,044,774 Corbin et al. 4,686,991 Dufresne et al. 4,379,462 Borkan et al. 4,688,574 Dufresne et al. 4,459,989 Borkan 4,719,499 Padjen et al. 4,492,233 Petrofsky et al. 4,750,499 Hoffer 4,512,351. Pohndorf 4,754,759 Allocca 4,759,368 Spanton et al. ______________________________________ Russian Patent No. 596,247 Jobling et al., "Electronic Aspects of SpinalCord Stimulation in Multiple Sclerosis", Medical & Biological Engineering & Computing Journal, January 1980, pp. 48-56. GarciaRill, E., "The basal ganglia and the locomotor regions", Brain Res. Rev., 11:47-63, 1986; GarciaRill, E. and R.D. Skinner, "The mesencephalic locomotor region. I. Activation of a medullary projection site", Brain Res., 411:1-12, 1987a; GarciaRill, E. and R.D. Skinner, "The mesencephalic locomotor region. II. Projections to reticulospinal neurons", Brain Res., 411:13-20, 1987b; GarciaRill, E., R.D. Skinner and J.A. Fitzgerald, "Chemical activation of the mesencephalic locomotor region", Brain Res., 330:43-54, 1985; Sherwood, A.M., "Spinal Cord Stimulation", The Encyclopedia of Medical Devices and Instrumentation, J. Webster, Ed., Wiley & Son, New York, Vol. 4, pp. 2652-2667,1988; "Control of walking and running by means of electrical stimulation of the midbrain", Biophysics, 11:756-765, 1966; an Skinner, R.D. and E. GarciaRill, "The mesencephalic locomotor region (MLR in the rat", Brain Res.. 323:385-389, 1984.
Jobling et al. disclose experiments using spinal-cord stimulation for cases of multiple sclerosis. Electrodes were placed in the mid-line of the posterior epidural space at the mid or upper thoracic level. Stimuli were applied at a frequency of 33 Hz with pulse durations between 0.05 msec and 2.0 msec. The electrical stimulation produced improved bladder sensation and control and, also, motor power and endurance. It should be noted that these patients could walk voluntarily without the need for stimulation and the stimulation was used only to help control untoward movements.
The Russian patent discloses the use of spinal-cord stimulation using pulses of 400 to 450 msec duration with an amplitude of 4-12 volts. This is an example of electrical stimulation being used to promote recovery from trauma, and not for specific motor control.
Borkan discloses a non-invasive multiprogrammable tissue stimulator which can be used to stimulate the cervical area of the spinal cord, the brain, the cerebellum or the individual nerve fibers or bundles thereof to elicit motor, sensory, neurologic, physiologic or psychological responses. According to this patent, the subcutaneously implanted receiver can be non-invasively programmed any time after implantation to stimulate different electrodes or change stimulation parameters such that a desired response can be attained. Although the patent mentions the possibility of using the device to stimulate the cervical area of the spinal cord to elicit motor responses, the patentee does not discuss the signal ranges which are available using his device, nor does he indicate which, if any, signal value will actually induce locomotion. Further, the motor responses referred to incidently by the patentee are merely unconnected movements. The patentee does not indicate that he can elicit locomotion, which is a specific pattern of movements which are, in their full form, stepping movements.
Charmillot et al. disclose the treatment of neurovegetative disorders by applying electrically induced energy to the brain. The specific electromagnetic wave energy disclosed in the patent consists of rectangular d.c. pulses having a pulse duration of 0.5 to 5 msec and a voltage of from 10 to 100 mv with a repetition frequency of from 10 to 100 Hz and a.c. pulses having a frequency of from 20 to 100 MHz modulated with a frequency of modulation of from 2.5 to 6,000 Hz. This method of stimulation of the brain is aimed at treating complex behavioral problems, not the control of movement.
Allocca discloses an apparatus and method for generating a train of up and down and up-staircase shaped electrical pulses whose peak negative amplitude is two-thirds of its peak positive amplitude and whose frequency can be varied between 1 Hz and 1,000 Hz, and applying these electrical pulses to the body for the treatment of nerve function, impairment and pain. No claims of locomotion control are made.
Padjen et al. disclose a stimulator for muscle stimulation or cranial electro-therapy stimulation. While the embodiment described relates to an instrument maintained externally to the patient, the patentee states that "a similar instrument can be internally implanted within the patient to provide direct stimulation on the nerves or spinal-cord." No indication is given as to the various values for the parameters as possible through the use of the device, especially in terms of the control of movement.
Mark discloses a device for treating sea sickness which involves the application of electrical stimulation to the patient's skull. The variable timing generator provides a frequency range that is variable between 1 and 5 pulses per second. The impulse generator is adjustable between 100 and 300 msec, with the current being adjustable between 0.5 and 3.8 mA. Locomotion control is not discussed.
Stasz et al. disclose a body stimulation system which uses implantable electrodes to stimulate internal portions of the body. Preferably, the low frequency range generated by the transmitter is from about 2 kiloherz to approximately 10 kiloherz. The system is used for stimulating the peroneal nerve in paraplegics, but no claims are made as to how such a stimulation is useful in controlling walking movements.
Zilber discloses an electrical spinal cord stimulating device for treatment of pain. The transmitter in this device is designed to transmit a rectangular pulse of approximately 250 msec. in duration with a repetition rate of from 5 to 200 pulses per second. Control of movement with such a device is not discussed.
A number of the patents listed disclose stimulators without disclosing the ranges of the stimulation parameters which are available through the use of the devices. The Spanton et al. and Dufresne et al. patents disclose electrical stimulators for the treatment of pain. Stanton discloses a tissue stimulator for stimulating muscles using electrodes implanted along the sides of the spine. Hansjurgens et al. disclose a device for electro-stimulation therapy.
Petrofsky and Hoffer disclose the use of electrical stimulation systems for "restoring" motor function of paralyzed muscles. The idea behind these stimulators is to induce locomotor-like movements by stimulating different muscles to contract at different times to produce walking movements. This requires that a program of the sequence of muscle contractions be intrinsic to the device. While this method could produce a rough form of walking, muscles or parts of muscles deep below the skin are difficult to activate and stepping can appear fragmented. In addition, very high currents are required to cause muscular contraction, and the effects of such currents on the underlying skin, muscle and nerve tissue are yet to be determined.
A variety of electrodes are known which can be implanted for applying electrical stimulation to the spinal cord as discussed above for the treatment of pain. Several of these electrodes are shown by Borkan et al., Avery et al., Corbin et al., and Hagfors.
Pohndorf discloses an introducer for a neurostimulator lead which is to be inserted into the epidural space of the spinal cord.
None of these stimulators disclose a device by which electrical pulses having a relatively long duration between 0.2 msec and 2 msec and a low frequency between 0.5 Hz and 20 Hz can be applied directly to the spinal cord in order to induce locomotion.
Over 20 years ago, experiments in the decerebrate cat revealed that stimulation of an area in the posterior midbrain induced normal-type locomotion on a treadmill (Shik et al., 1966). This area was termed the Mesencephalic Locomotor Region (MLR). During the past eight years, the first-named inventor has been working on the anatomical connections of the MLR (for review, see Garcia-Rill, 1986), demonstrating its presence in the rodent brain (Skinner and Garcia-Rill, 1984), and discovering that localized injections of neurotransmitters injected into the MLR could be used to induce locomotion (Garcia-Rill et al., 1985). Recently, the main descending projection target of the MLR, the medioventral medulla (MED), was reported to induce locomotion following electrical and chemical activation (Garcia-Rill and Skinner, 1987a, 1987b). The studies in the laboratory of the present inventors, then, have progressed from the midbrain to the medulla, and now, by the present invention, to the spinal cord.
The methods previously used to improve locomotion by electrically stimulating the muscles, either with implanted electrodes or with external electrodes, have significant disadvantages in their practical application. In particular, as briefly discussed above, very high currents are required in order for movement to occur. These large currents may cause irreparable damage to the nerve and/or muscle tissue in the former case and to the skin in the latter. Further, in order to take a step, a large number of muscles are involved which must be stimulated in a particular sequence. It is very difficult, in fact, nearly impossible to duplicate the normal sequence by merely stimulating the muscles. Additionally, if not all the muscles involved in the walking process are stimulated, the method will not be effective in producing normal-type walking. Since there are a large number of muscles involved, it is nearly impossible to stimulate them all in the proper sequence.
Previous investigations, using brainstem stimulation to induce walking, revealed that very low current levels applied to localized areas of the brainstem can produce normaltype walking. That is, the full range of muscular contractions were elicited in the required pattern for a single step by electrically stimulating the brainstem. This locomotor pattern for producing locomotion is generated at the level of the spinal cord. That is, the full program of muscular contractions is found in spinal pattern generators which are located in the cervical and lumbar enlargements of the spinal cord. Brainstem stimulation merely triggers this preprogrammed pattern of contractions.
The methods involving direct stimulation to the midbrain or the medulla, however, have significant problems in clinical application. Even if it were possible to have a living person implanted with electrodes in their brain, the location of the MLR and MED in relation to respiratory and cardiovascular control centers makes such implants undesirable. In cases of paralysis by damage to the spinal cord, downstream from the midbrain or medulla where the stimulation is applied, the necessary triggering signal does not reach the spinal cord and muscles. Therefore, these techniques will not be effective to actually stimulate locomotion following complete transection of the spinal cord. The use of electrical stimulation of the spinal cord to induce walking as disclosed in the present application represents an effective way of directly activating the intrinsic spinal pattern generators for locomotion, with concomitant manifestation of the normal muscular contractions used in stepping.
As is clear from a study of the above-listed patents relating to electrical stimulators, the low frequencies and long duration pulses required to induce locomotion by direct spinal cord stimulation are outside, or at the edge of, the effective range of the parameters available from the devices conventionally known for the treatment of pain and movement disorders.